116.1: Evidence for platelet-derived transforming growth factor-beta1 as an early inducer of liver regeneration after hepatectomy in mice

Animal and clinical evidence indicates that platelets modulate liver regeneration, notably through degranulation of platelets in liver sinusoids. This study was conducted to analyze whether platelet-derived TGFβ1 regulates liver regeneration early after 2/3 partial hepatectomy (PHx). Hepatocyte proliferation, IL6 and HGF responses, liver gene expression and platelet kinetics, were analyzed after PHx in wild-type (WT) and in platelet-specific TGFβ1 knock-out (Plt.TGFβ1 KO) mice. Moreover, circulating levels of TGFb1 and Thrombopoietin were measured. Platelet-TGFβ1 deficiency led to strong reduction of proliferating hepatocytes. At 48h and 72h after PHx, 49.2 ± 19.0% and 29.3 ± 12.6% Ki67-positive hepatocytes were detected in WT mice, compared to 15.6 ± 21.3% and 17.0 ± 10.9%, respectively, in Plt.TGFβ1 KO mice (mean ± SD, p<0.0001). In Plt.TGFβ1 KO mice, decreased hepatocyte proliferation were paralleled with decreased median IL6 serum levels at 5h and increased HGF levels at 48h, compared to WT mice. Circulating total plasma TGFβ1 levels were significantly higher in WT mice increasing from 7.4 ± 3.5 ng/ml to 21 ± 13 ng/ml at 0 and 5h after HPx, when compared to Plt.TGFβ1 KO mice with values increasing from 2.9 ± 0.5 ng/ml to 7.0 ± 2.1 ng/ml, respectively (p=0.0031). Platelet numbers decreased in WT mice whereas in Plt.TGFβ1 KO mice platelet numbers remained unaltered, with significant higher numbers at 48h compared to WT mice. This was paralleled with an earlier increase in liver Thrombopoietin expression in Plt.TGFβ1 KO compared to WT mice (p=0.0308) suggesting that platelet-derived TGFβ1 negatively impacts hepatic Thrombopoietin production during liver regeneration. In conclusion, platelet-TGFβ1 regulates key mitogenic cytokines in the early phase of liver regeneration, therefore early TGFβ1 administration might be useful for promoting liver regeneration. Acknowledgments to the Swiss Science Foundation: FN-4121/ CRSK-3_196301/1.